Review article
CD147/basigin promotes progression of malignant melanoma and other cancers

https://doi.org/10.1016/j.jdermsci.2009.12.008Get rights and content

Abstract

CD147/basigin, a transmembrane protein belonging to the immunoglobulin super family, was originally cloned as a carrier of Lewis X carbohydrate antigen. CD147 is strongly related to cancer progression; it is highly expressed by various cancer cells including malignant melanoma (MM) cells and it plays important roles in tumor invasiveness, metastasis, cellular proliferation, and in vascular endothelial growth factor (VEGF) production, tumor cell glycolysis, and multi-drug resistance (MDR). CD147 on cancer cells induces matrix metalloproteinase expression by neighboring fibroblasts, leading to tumor cell invasion. In a nude mouse model of pulmonary metastasis from MM, the metastatic potential of CD147-expressing MM cells injected into the tail vein is abolished by CD147 silencing. CD147 enhances cellular proliferation and VEGF production by MM cells; it promotes tumor cell glycolysis by facilitating lactate transport in combination with monocarboxylate transporters, resulting in tumor progression. CD147 is responsible for the MDR phenotype via P-glycoprotein expression. These findings strongly suggest CD147 as a possible therapeutic target for overcoming metastasis and MDR, major obstacles to the effective treatment of malignant cancers.

Introduction

Malignant cancers are characterized by immortalized cellular proliferation, activated invasiveness into the surrounding stroma, distant metastasis, and angiogenesis via vascular endothelial growth factor (VEGF) production. Cancer cells often acquire resistance to anticancer drugs; these cells are of the multi-drug resistance (MDR) phenotype. Distant metastasis and MDR, the major obstacles to the effective treatment of malignant cancers, remain to be overcome.

CD147/basigin (Bsg), an integral plasma membrane protein belonging to the immunoglobulin superfamily, is expressed widely in various embryonic and adult tissues [1], [2]. Because of its ubiquitous distribution, it is thought to play fundamental roles in the regulation of various cellular activities. Molecules identical to Bsg were discovered and given different names, i.e. M6 [3] and EMMPRIN [4] in humans, HT7 [5], neurothelin [6], and 5A11 [7] in chickens, pg42 [8] in mice, and OX-47 [9] and CE9 [10] in rats. They turned out to be multifunctional and involved in various physiological processes such as fetal development, reproduction, T cell differentiation, and neural and retinal functions [11], [12]. There is growing evidence that Bsg expression is highly increased in various tumor cells [13], [14], [15], [16], [17], [18], [19] including malignant melanoma (MM) [20]. The elevated expression of Bsg in cancer cells suggests it as a pivotal regulator of tumorigenesis. Indeed, Bsg was found to be functionally involved in tumor invasiveness, metastasis, growth, and angiogenesis and to regulate glycolysis and MDR [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31]. Here we review the function of Bsg in regulating tumor progression in human malignant tumors including MM.

Section snippets

Cloning of CD147/basigin and related molecules

Cell surface glycoproteins regulate cellular growth and differentiation and serve as surface markers. The cell surface marker Lewis X antigen is expressed in embryonal carcinoma (EC) cells; it is not found in most cells differentiated from EC cells. CD147/basigin, identified as a new member of the immunoglobulin (Ig) superfamily, was initially cloned as a carrier of Lewis X carbohydrate antigen in teratocarcinoma stem cells in a study of a developmentally regulated cell surface marker [1]. We

Invasiveness of malignant melanoma

The possible role of CD147 in invasion in association with MMP expression was investigated using human MM specimens and the human MM cells KHm-1/IV and G361, that highly express CD147 compared to normal human melanocytes (NHMCs). Immunohistochemically, there are significant positive correlations between the level of CD147 expression in MM cells and the expression of MMPs; MMP-1 (collagenase), MMP-2 (gelatinase), MMP-3 (stromelysine), and MT1-MMP (membrane type MMP) in fibroblasts surrounding

CD147/basigin and glycolysis

CD147 is an important molecule for tumor progression including tumor invasiveness, metastasis, proliferation, and angiogenesis. The common mechanisms underlying these functions have been addressed.

Glycolysis is enhanced in tumor cells [40]. Under physiological conditions, it is the result of an anaerobic enzymatic conversion of glucose to pyruvate or lactate to produce energy stored in the form of adenosine triphosphate (ATP). Warburg [41] first reported that cancer cells depend on glycolysis

CD147/basigin and multi-drug resistance

Multi-drug resistance and metastasis, the major obstacles to the effective treatment of malignant cancers, have been studied extensively and the functional linkage between these two phenotypes has been reported. Yang and co-workers [27], [28] who used a human mammary carcinoma cell line (MCF7) and its MDR counterpart (MCF7/Adr) found that CD147 connects these two phenotypes. The MDR phenotype of MCF7/Adr cells is primarily attributable to P-glycoprotein (P-gp), an ATP-dependent transmembrane

Conclusion

CD147, originally cloned as a carrier of Lewis X carbohydrate antigen in a study of a developmentally regulated cell surface antigen, plays important roles in the various processes of tumor progression including cellular proliferation, invasiveness, metastasis, angiogenesis, tumor cell glycolysis, and MDR phenotypes, emerging as a potential target for cancer therapy. However, additional studies to induce the localized expression of CD147 in cancer cells are needed because CD147-null mice show

References (52)

  • V.R. Fantin et al.

    Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance

    Cancer Cell

    (2006)
  • M. Baba et al.

    Blocking CD147 induces cell death in cancer cells through impairment of glycolytic energy metabolism

    Biochem Biophys Res Commun

    (2008)
  • V. Yurchenko et al.

    CD147 is a signaling receptor for cyclophilin B

    Biochem Biophys Res Commun

    (2001)
  • T. Miyauchi et al.

    Basigin, a new, broadly distributed member of the immunoglobulin superfamily, has strong homology with both the immunoglobulin V domain and the β-chain of major histocompatibility complex class II antigen

    J Biochem

    (1990)
  • T. Kanekura et al.

    Basigin, a new member of the immunoglobulin superfamily: genes in different mammalian species, glycosylation changes in the molecule from adult organs and possible variation in the N-terminal sequences

    Cell Struct Funct

    (1991)
  • W. Kasinrerk et al.

    Human leukocyte activation antigen M6, a member of the Ig superfamily, is the species homologue of rat OX-47, mouse basigin, and chicken HT7 molecule

    J Immunol

    (1992)
  • C. Biswas et al.

    The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily

    Cancer Res

    (1995)
  • H. Seulberger et al.

    The inducible blood–brain barrier specific molecule HT7 is a novel immunoglobulin-like cell surface glycoprotein

    EMBO J

    (1990)
  • B. Schlosshauer et al.

    Neurothelin: an inducible cell surface glycoprotein of blood–brain barrier-specific endothelial cells and distinct neurons

    J Cell Biol

    (1990)
  • J.M. Fadool et al.

    5A11 antigen is a cell recognition molecule which is involved in neuronal-glial interactions in avian neural retina

    Dev Dyn

    (1993)
  • S. Fossum et al.

    The MRC OX-47 antigen is a member of the immunoglobulin superfamily with an unusual transmembrane sequence

    Eur J Immunol

    (1991)
  • C.L. Nehme et al.

    Breaching the diffusion barrier that compartmentalizes the transmembrane glycoprotein CE9 to the posterior-tail plasma membrane domain of the rat spermatozoon

    J Cell Biol

    (1993)
  • T. Muramatsu et al.

    Basigin (CD147): a multifunctional transmembrane protein involved in reproduction, neural function, inflammation and tumor invasion

    Histol Histopathol

    (2003)
  • L.C. Bordador et al.

    Expression of EMMPRIN by oral squamous cell carcinoma

    Int J Cancer

    (2000)
  • K. Muraoka et al.

    Enhanced expression of a tumor-cell-derived collagenase-stimulatory factor in urothelial carcinoma: its usefulness as a tumor marker for bladder cancers

    Int J Cancer

    (1993)
  • M. Polette et al.

    Tumor collagenase stimulatory factor (TCSF) expression and localization in human lung and breast cancers

    J Histochem Cytochem

    (1997)
  • Cited by (87)

    • Targeted degradation of CD147 proteins in melanoma

      2020, Bioorganic Chemistry
      Citation Excerpt :

      CD147 is a transmembrane glycoprotein and a member of immunoglobulin superfamily [3,4]. It is a tumor-associated antigen that is highly expressed in various tumors, including malignant melanoma (MM) [5–10]. CD147, which is also called extracellular matrix metalloproteinase inducer (EMMPRIN), overexpression of CD147 has a significant association with the expression of matrix metalloproteinase (MMP), and it also reported to be an association with vascular endothelial growth factor (VEGF) [10–12].

    • CD147 Is a Novel Chemotherapy or Prevention Target in Melanoma

      2018, Journal of Investigative Dermatology Symposium Proceedings
    View all citing articles on Scopus
    View full text